Synthetic studies on the azinothricin family of antitumour antibiotics

This thesis consists of five sections. The first four discuss chemistry that is relevant to a total synthesis of the antitumour antibiotic A83586C that is being carried out in these laboratories. The fifth describes the preparation of some new pyranoid 5,6-glycals from methyl β-D-fructopyranoside. In the first section, we outline a method for preparing 2,3-O-cyclohexylidene-2-C-ethyl-(2R)-glyceraldehyde utilising Sharpless asymmetric dihydroxylation (AD) chemistry. This intermediate was then used for constructing the C(28)-C(47) segment of antibiotic A83586C. In the second section, we describe our studies on the Sharpless asymmetric dihydroxylation (AD) reactions of 1,1-disubstituted allyl alcohol and phenylsulfide derivatives. In the majority of systems examined, the product diols had ee's in the 11-91% range and possessed absolute stereochemistry opposite to that predicted by the Sharpless face-selection rule. The third chapter discusses a practical new asymmetric synthesis of both enantiomers of erythro-3-hydroxyleucine, that is again based on Sharpless AD chemistry. By this route, (2S,3S)-(+)-3-hydroxyleucine was obtained in 97% ee and 67% overall yield, while the (2R,3R)-(-)-enantiomer was isolated in 92% ee and 57% overall yield. In the fourth section, a new three-step asymmetric synthesis of (3R)-piperazic acid is described. The key steps in this route were the electrophilic hydrazination of a chiral bromovaleryl carboximide enolate with di-tert-butyl azodicarboxylate, and the subsequent intramolecular SN2 displacement of the bromide group to close the hydrazine ring system. The diastereoselectivity of this process was typically greater than 96%. (3R)-Piperazic acid is a key component of antibiotic A83586C. The final chapter discusses some new methodology for the efficient construction of pyranoside 5,6-glycal derivatives of methyl β-D-fructopyranoside

Total Synthesis of the GRP78-Downregulatory Macrolide (+)-Prunustatin A, the Immunosuppressant (+)-SW-163A, and a JBIR- 04 Diastereoisomer That Confirms JBIR-04 Has Nonidentical Stereochemistry to (+)-Prunustatin A

A unified total synthesis of the GRP78-downregulator (+)-prunustatin A and the immunosuppressant (+)-SW-163A based upon [1 + 1 + 1 + 1]-fragment condensation and macrolactonization between O(4) and C(5) is herein described. Sharpless asymmetric dihydroxylation was used to set the C(2) stereocenter present in both targets. In like fashion, coupling of the (+)-prunustatin A macrolide amine with benzoic acid furnished a JBIR-04 diastereoisomer whose NMR spectra did not match those of JBIR-04, thus confirming that it has different stereochemistry than (+)-prunustatin A